Safety and Effectiveness of Liv.52 DS in Patients With Varied Hepatic Disorders: An Open-Label, Multi-centre, Phase IV Study

Background The hepatoprotective function of polyherbal formulation Liv.52 in chronic liver diseases is well recognized in published literature. The objective of this open-label, phase IV study was to further strengthen and validate its safety and effectiveness using a large patient pool in a real-world scenario and provide scientific data on symptomatic improvement and supportive treatment in liver function with improvement in quality of life. Methods Adult patients of either sex with one or more clinical symptoms like fatigue, nausea, anorexia, abdominal pain or discomfort, muscle cramps, jaundice, or any other signs and symptoms with a history suggestive of mild-to-moderate hepatic disorders like alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), drug-induced hepatotoxicity, or hepatitis were treated with two Liv.52 DS tablets (oral) twice daily for 12 weeks. Results Out of the 1000 enrolled patients, 962 (96%) completed the study with the following subgroups ALD: 375 (38.9%), NAFLD: 379 (39.3%), drug-induced hepatotoxicity: 78 (8.1%), hepatitis: 130 (13.5%). The mean age of enrolled patients was 37.7 years, and the majority of them, 785 (78.5%) were men. The common adverse events observed (with >1.5% incidence) in the study were abdominal pain: 26 (2.6%) and headache: 17 (1.7%). Liv.52 showed statistically significant improvement (P<0.0001) in various clinical signs and symptoms in the majority of patients namely, fatigue: 357/723 (49%), anorexia: 485/620 (78.2%), jaundice: 48/52 (92%). Majority of the patients showed significant improvements from baseline to end of 12 weeks in the liver function test parameters namely, aspartate aminotransferase: 633/840 (75.36%), alanine aminotransferase: 592/729 (81.21%), serum bilirubin: 244/347 (70.32%), alkaline phosphatase: 279/355 (78.59%) with P<0.0001 for all parameters. Statistically significant improvement (P<0.005) was also seen in all the components of the chronic liver disease questionnaire (CLDQ) scores from baseline to 12 weeks. Conclusions The study demonstrated that Liv.52 was hepatoprotective and well tolerated in the study population after treatment for 12 weeks. Significant improvements were seen in clinical signs and symptoms, laboratory parameters of liver function, and CLDQ scores from baseline to 12 weeks. No significant or new safety signals emerged from this study.


Introduction
Chronic liver disease (CLD) affects >800 million individuals globally, leading to over two million deaths each year, accounting for 4% of all deaths worldwide [1].Liver disease ranks as the 11th most prominent factor contributing to mortality and the 15th leading cause of disability-adjusted life-years.The highest impact is on patients aged between 25 to 49 years [2].Overall liver disease leads to two million worldwide deaths, of which 18.3% are from India [3].
The progression of CLD starts with inflammation, followed by fibrosis with impaired normal functioning.The final stage is cirrhosis or scarring of the liver tissues, which is associated with a significant compromise of liver function [4].Based on the etiology and pathogenesis, CLDs are classified into different types; the most common being alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) or metabolicassociated fatty liver disease (MAFLD), drug-induced hepatotoxicity (DIH), and chronic viral hepatitis [5].Pharmacological interventions to manage CLD may include antiviral drugs (viral hepatitis), corticosteroids, and immunosuppressive agents (autoimmune hepatitis) apart from symptomatic management [4].However, long-term use of antiviral medications has been associated with hepatotoxicity and antiviral resistance [5,6], while long-term use of immunosuppressants increases the risk of infections and causes metabolic disturbances [4,7].This necessitates the identification and development of alternative medicines that are hepatoprotective in function and are less toxic or safe for long-term use.
Liv.52 is a polyherbal licensed ayurvedic medicine from the traditional system of medicine.Liv.52 is shown to be hepatoprotective, antioxidant, antiviral, and anti-inflammatory in function.As per the available information, it is indicated in the symptomatic improvement and supportive treatment of mild-to-moderate ALD, viral hepatitis, NAFLD, and DIH [7].Liv.52 might be used as an adjuvant to other medications known for causing DIH (anti-tubercular drugs, antiretrovirals, chemotherapeutic agents, statins) [6][7][8].Although the hepatoprotective function of Liv.52 in liver diseases is well recognized, the objective of this study was to further strengthen and validate its safety and effectiveness on a larger patient pool in a real-world scenario in scattered geography.It was aimed to generate clinical data related to symptomatic improvement, impact on quality of life (QOL), liver enzymes, and to assess the safety with higher doses (Liv.52 DS, two tablets, twice daily) when used in varied hepatic disorders.

Study design and ethical considerations
This open-label, single-arm, phase IV study was conducted from August 2022 to July 2023 at 37 sites across eight cities in India.The study protocol (CTRI registration number: CTRI/2022/08/044545) was reviewed and approved by the independent ethics committees at all participating sites (details of which have been provided in Appendices Table 4).The study was conducted in full compliance with ethical principles laid down by the World Medical Association -Declaration of Helsinki (Oct 2013) for medical research involving human subjects, Guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) -Good Clinical Practices (GCP), 'Ethical-Guidelines for Biomedical Research on Human Subjects' issued by Indian Council of Medical Research (2017) and the applicable regulatory requirement in India (Schedule 'Y') and Central Council for Research in Ayurvedic Sciences.All patients provided written informed consent before participation in the study.As this was a Phase IV study, there was no formal sample size calculation planned.To meet the objective of validating the safety and effectiveness of the test product using a large patient pool in a real-world scenario a sizeable number of 1000 patients were planned to be enrolled in the study.

Study population
Patients (>18 years old) of either sex with one or more clinical symptoms like fatigue, nausea, anorexia, abdominal pain or discomfort, muscle cramps, jaundice, or any other symptoms with a history suggestive of mild-to-moderate hepatic disorder like ALD, which is characterized with a history of persistent alcohol intake and with liver function tests (LFT) suggestive of liver disease, NAFLD (patients with a history suggestive of impaired metabolic function and the final diagnosis was made through exclusion), DIH (patients with the specific history of drug intake attributed to causing liver injury like anti-tubercular, antiretroviral therapies etc.) or hepatitis (patients with elevated LFT suggestive of hepatitis) were enrolled in the study as per protocol defined eligibility criteria.Patients of child-bearing potential were enrolled only if they agreed to use adequate and validated contraception during the study period.Patients suffering from severe hepatic conditions or complications like hepatocellular carcinoma, chronic hepatitis (hepatitis B or hepatitis C), portal hypertension, splenomegaly, hepatic encephalopathy, confusion, swelling/bleeding from veins, fluid accumulation in the abdomen, non-alcoholic steatohepatitis with cirrhosis as well as those undergoing active treatment for alcohol withdrawal syndrome, or those with ongoing treatment for CLD were excluded from the study.Patients with normal LFT or those with highly elevated LFT defined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >5 times the upper limit for normal (ULN) or those with compromised hematological parameters (total white blood cells <3,000 cells/mm3, absolute neutrophils <1,500 cells/mm3, platelets <1,00,000/mm3) or patients with serum creatinine >2 mg/dL or creatinine clearance <60 mL/min (based on Modification of Diet in Renal Disease (MDRD)) at screening, were also excluded from the study.The study also excluded pregnant or lactating women and patients where prior treatment of Liv.52 DS was found to be ineffective or non-tolerable.

Study treatment
Eligible patients were treated with Liv.52 DS two tablets (oral) twice daily for 12 weeks or end of study (EOS).Safety evaluations included monitoring of adverse events (AEs) throughout the study.All AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA, Version 26.0).Clinical laboratory data for hematological and biochemical parameters, physical examinations, and vital signs were also evaluated.Efficacy evaluation included changes in LFT parameters (ALT, AST, bilirubin, and alkaline phosphatase (ALP) from baseline to EOS.The study also evaluated the changes in clinical signs and symptoms (fatigue, nausea, anorexia, abdominal pain or discomfort, muscle cramps, jaundice, and any other symptoms related to mildmoderate hepatic disorder) for all patients.Patient-reported QOL assessments were performed using the chronic liver disease questionnaire (CLDQ, 29 items in the following domains: abdominal symptoms, fatigue, systemic symptoms, activity, emotional function, and worry).All CLDQ responses were rated from one (denoting "all of the time") to seven (denoting "none of the time") for all patients.

Statistical analysis
Safety was analyzed for the safety analysis set (all patients who were allocated to treatment and received at least one dose of the study drug) and was summarized descriptively.Efficacy parameters were analyzed using the per-protocol (PP) analysis set (all patients who completed the study as per protocol).Continuous data were analyzed by paired t-test or Wilcoxon signed-rank test, wherever appropriate, for comparing pre-and post-treatment data.Categorical data like abnormal to normal shift and overall improvement were analyzed using McNemar's test and Z-test.All statistical tests and confidence intervals are two-sided unless otherwise stated, P<0.05 was considered significant.
All statistical analyses were performed using SAS® software (version 9.4, SAS Institute, Cary, USA).

Demographic characteristics
Adequate number of subjects were required to be screened to achieve the enrolment of 1000 subjects as per eligibility criteria.Overall, a total of 1,531 patients were required to be screened for eligibility to enrol 1,000 patients who were comprised of ALD: 387 (38.7%),NAFLD: 391 (39.1%),DIH: 85 (8.5%), hepatitis: 137 (13.7%) as per defined criteria.Most of the enrolled patients were nondiabetic 955 (95.5%) however, the remaining 45 (4.5%) patients did have diabetes.Of these, 962 (96%) patients completed the study (Figure 1).The mean age of the enrolled patients was 37.7 years; the majority were men: 785 (78.50%) and all patients were of Asian origin (Table 1).

Safety
Overall, 215 (21.5%) unique patients reported a total of 286 AEs, of which most AEs: 245 (85.6%) were of mild severity.Severity was assessed using Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).Causality assessment of these adverse events to confirm the relationship to the study drug was performed through the World Health Organization -Uppsala Monitoring Centre (WHO-UMC) causality assessment criteria.The treating investigators assessed that most of the AEs, 283 (98.9%) were not related to the study drug.Only three patients experienced three AEs, which were found to be related to study drug or adverse drug reactions mainly mild abdominal pain: 2 (0.2%) and moderate acidity: 1 (0.1%).Two serious adverse events (SAEs) were also reported during the study (death -one case of road traffic accident, and one case of worsening of tuberculosis).However, none of the SAEs were found to be related to the study treatment.

TABLE 2: Summary of Adverse Events
ADRs: Adverse drug reactions; AE: Adverse events; SAEs: Serious adverse events.

Liver function test (LFT): overall impact
A significant improvement (P<0.0001) was observed in all LFT parameters (from baseline to EOS).The mean (SD) AST level reduced from 113.7 (98.20)U/L at baseline to 37.0 (39.30)U/L at 12 weeks in the study.Out of 840 patients who had elevated AST levels at baseline, 633 (75.36%) patients returned to normal at EOS.Likewise, the mean (SD) ALT levels also reduced significantly from 123.8 (89.01)U/L at baseline to 36.9 (53.64)U/L at EOS.Out of 729 patients who had elevated ALT levels at baseline, 592 (81.21%) patients returned to normal at EOS.Similarly, most of the patients, 244/347 (70.32%) showed improvements in their bilirubin levels and 279/355 (78.59%) in ALP levels from baseline to EOS.Similar patterns were observed in all subgroups of patients for all LFT parameters (Appendices Table 5 and Figures 2, 3). Figure 2 shows the average percent reduction in LFT values in patients, who had abnormal values at baseline, and Figure 3 shows the patient-wise shift of abnormal values of LFT parameters at baseline to normal LFT values at EOS.

LFT in patients with ALD
Overall, patients with abnormal AST (n=320), ALT (n=264), bilirubin (n=153), and ALP (n=123) values at baseline demonstrated a significant reduction of 52.88%, 59.93%, 26.01%, and 27.86%, respectively at EOS (all P<0.0001) (Figure 2B). Figure 3B shows that a majority of patients had a shift from abnormal to normal LFT parameters at EOS.Additionally, 81 out of 113 patients (71%) with ALD had their AST/ALT ratio shifted from >1.5 to ≤1.5 at EOS, and all 43 patients (100%) of ALD with elevated bilirubin levels (>3 mg/dL) at baseline had their levels returned to ≤ 3 mg/dL at EOS, thereby suggesting normalization of altered liver function in ALD [9].

LFT in patients with NAFLD
A total of 337 patients with abnormal AST, 299 patients with abnormal ALT, and 165 patients with abnormal ALP values at baseline had their AST, ALT, and ALP levels reduced by 52.22%, 58.05%, and 28.97% respectively, at EOS (all P<0.0001) (Figure 2C). Figure 3C indicates the overall majority of patients demonstrated a shift from abnormal to normal LFT parameters at EOS.

LFT in patients with NAFLD and diabetes
Ten patients with abnormal AST, 12 patients with abnormal ALT, 4 patients each with abnormal bilirubin and ALP levels at baseline demonstrated a 38.3%, 46.5%, 16.7%, and 15.3% reduction in AST (P<0.0277),ALT (P<0.0091),bilirubin, and ALP levels respectively at EOS (Figure 2D).The majority of patients in this subgroup showed a shift to normal LFT parameters at EOS (Figure 3D).

LFT in patients with DIH
A total of 70 patients with DIH and abnormal AST values at baseline had their AST levels reduced by 58.61% at EOS (P<0.0001).Similarly, 65 patients with abnormal ALT, 24 patients with abnormal bilirubin levels, and 29 patients with abnormal ALP levels at baseline demonstrated 72.09%, 47.38%, and 45.31% reduction in their ALT, bilirubin, and ALP levels respectively at EOS (all P<0.0001) (Figure 2E).Majority of the patients had a shift to normal LFT parameters at EOS (Figure 3E).
A subgroup analysis was also performed for patients with DIH due to anti-tubercular and anti-retroviral treatment.Sixteen patients with DIH due to anti-tuberculosis treatment reported a change in mean value from 202 U/L to 61 U/L or a reduction of 141 U/L (70%) in mean ALT levels from baseline within 2-3 weeks (P<0.0001),indicating the preliminary trend of the efficacy of the study drug within 2-3 weeks in this subgroup.Similarly, higher level of ALT and AST, in 15 patients with DIH due to retroviral therapy was also significantly reduced at 12 weeks.

LFT in patients with hepatitis
Overall, 113 patients with abnormal AST levels at baseline reported a 58.07%reduction in AST levels at EOS (P<0.0001).Similarly, 101 patients with abnormal ALT, 45 patients with abnormal bilirubin, and 38 patients with abnormal ALP levels at baseline reported 66.28%, 17.5%, and 8.29% reduction in their ALT, bilirubin, and ALP levels at EOS respectively (P<0.0001 for all) (Figure 2F).The number of patients who demonstrated a shift from abnormal LFT parameters to normal at EOS is presented in Figure 3F.

Impact on anemia of chronic disease (ACD)
Out of 213 patients with low hemoglobin (male <12 gm/dL, female <10 gm/dL) at baseline, 62 (29.1%) had their mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) values normal, which clinically indicates a probable case of ACD.In these 62 (29.1%) patients, statistically significant improvements in mean hemoglobin levels (baseline: 10.8 gm/dL; EOS: 12.54 gm/dL; P<0.0001) were observed.Although ACD cannot be confirmed solely based on blood count alone, these results show an encouraging trend, which can be explored further in iron profiling studies.

Clinical signs and symptoms
Overall, most of the patients with clinical symptoms at baseline became symptom-free at EOS. Amongst patients who had symptoms of fatigue/tiredness/weakness at baseline, 357 (49%) out of 723 were found to be symptom-free at EOS.Of patients with symptoms of nausea at baseline, 419 (79.3%) out of 528 became symptom-free at EOS.Among patients with abdominal pain symptoms and muscle cramps at baseline, 583 (76%) and 297 (71%) patients became symptom-free at EOS, respectively (Table 3).

Signs and symptoms (N)
No (%) of patients with signs and symptoms at baseline who remained with signs and symptoms at

Quality of life assessment
The mean CLDQ scores (overall and subdomains) improved significantly from baseline to EOS (Figure 5 and Appendices Table 6).

Discussion
This open-label, phase-IV study demonstrated that Liv.52 was well tolerated and was hepatoprotective in patients with varied hepatic disorders in the study population.Statistically significant (P<0.0001)improvements were seen in clinical symptoms and liver enzyme parameters studied, from baseline to EOS, in the overall population as well as in all four subgroups of patients (ALD, NAFLD, DIH, hepatitis).Most of the patients in this study who had abnormal levels of liver enzymes at baseline became normal after the treatment with the study drug for 12 weeks.This statistical significance was translated into clinical significance, which was evident through improvement in signs, symptoms, and QOL of the participating patients.
Among 113 patients with ALD, 81 (71%) patients demonstrated a shift in their AST/ALT ratio from >1.5 to <1.5, and all 43 patients (100%) with significantly high bilirubin levels (>3 mg/dL) shifted to <3 mg/dL at EOS.The outcome of both the parameters in ALD, suggests normalization of altered liver function following the intervention of Liv.52, although this may be attributed to uncertainty (which is beyond control on outpatient studies) of alcohol consumption and abstinence in these patients [9].Normalization of LFT in patients with DIH is usually observed following the discontinuation of ongoing treatments (antituberculosis treatment anti-retroviral therapies or any other drug).However, in the current study, normalization could be achieved in patients, even after the continuation of their ongoing respective therapies.Additionally, improvement in LFT was also seen in the patients who had DIH due to other drugs like NSAIDS (etoricoxib), hypouricemic drug (febuxostat), DMARDs (hydroxychloroquine, sulfasalazine), and immunosuppressant (methotrexate).This is an important observation suggesting the hepatoprotective function of Liv.52 in such patients with DIH.However, more studies are warranted with a larger sample size to establish the hepatoprotective role of Liv.52 as an adjuvant with anti-tubercular or anti-retroviral therapies for the prevention and treatment of DIH.
Overall, our results were consistent with the earlier published studies demonstrating the hepatoprotective function of Liv.52 [8,10,11].Liv.52 is known to decrease intrahepatic edema inhibiting necrosis; thereby relieving intrahepatic cholestasis and aiding the regeneration of hepatic cells [7].It is also known to help in membrane stabilization by normalization of sodium-potassium-ATPase in the liver [11].These activities directly or indirectly affect cellular and metabolic functions, including inhibition of oxidative DNA degradation, free radical scavenging, hydrogen peroxide inhibition, iron chelation, downregulation of tumor necrosis factor-α, replenishment of growth-stimulating hormone levels in the hepatocytes, and strong antiviral activity inhibiting viral attachment and penetration [12,13] and thus helps in maintaining the integrity of liver tissue and restoring its function [10].
Liv.52 is also known to effectively reverse the metabolic and histological changes associated with high-fat diet-induced NAFLD [14].Consistent with this, in the current study, Liv.52 was effective in not just relieving the associated clinical signs and symptoms and reducing the LFT levels significantly in patients with NAFLD but was also found to be effective in abnormal to normal shift of liver parameters from baseline to EOS.NAFLD is strongly associated with obesity and type 2 diabetes mellitus (T2DM); it can be considered as the hepatic manifestation of the metabolic syndrome [15].There is a 1.87-fold increased risk of cardiovascular events in NAFLD in the presence of T2DM and increased diabetes-related microvascular complications such as chronic kidney disease and retinopathy [16].The present study noted a reduction in the clinical symptoms in patients of NAFLD with diabetes after treatment with Liv.52 for 12 weeks.However, considering the very low sample size, in this subgroup, larger studies are required to demonstrate the beneficial role of Liv.52 in this patient population.
A significant complication of CLD is malnutrition, due to poor dietary intake owing to anorexia.The current study found that out of 620 patients who had anorexia at baseline, 485 (78.23%) became symptom-free with respect to anorexia, following Liv.52 treatment.
Liver diseases can be exhausting for many patients due to their chronic nature.Assessing health-related QOL is important to understand the psychological, social, and functional aspects of the disease that directly impact everyday functioning [17].Furthermore, it has been demonstrated that QOL exhibits substantial clinically significant associations with liver function parameters (albumin, bilirubin, ALP, and albumin-to-ALP ratio).Hence, inadequate management can adversely affect survival in these patients [17,18].An improvement in liver parameters and the clinical signs and symptoms of liver diseases directly impacts the QOL of the patients.This correlation was evident in the current study, wherein improvements in LFT and clinical signs and symptoms were corroborated with improvements in CLDQ scores in all patients.
Safety of Liv.52 was further established as most AEs were mild in severity and unlikely related to the treatment.There was no treatment discontinuation due to AEs.Considering the large population size of this study, there were only three adverse drug reactions of mild-to-moderate severity.As per European Medical Association guidelines (summary of product characteristics, SmPC, 2009) such incidences of adverse drug reactions are termed as uncommon or infrequent.There were no treatment-emergent SAEs reported in the study.The safety information generated in this study is consistent with the known safety profile of Liv.52.
No new safety concerns emerged from the study showing no concern about using Liv.52 DS two tablets twice daily for 12 weeks.No concern of nephrotoxicity (as per the assessment of serum creatinine) was observed in the study.In a small patient population, 145 (14.5%) lack of efficacy was observed (elevation of liver parameters), which may be attributed to disease progression, lifestyle changes, or other co-morbidities.
There are approximately 40 commercial hepatoprotective polyherbal formulations that are available in the Indian market.However, evidence-based data can be found for only a few of these formulations [19].Of these, Liv.52 has been widely studied for the therapy of CLD [20].The outcome of the present study is in line with a phase IV study on liver care supplement ursodeoxycholic acid conducted in 235 patients with varied liver diseases (ALD, NAFLD, hepatitis) demonstrating a reduction in liver enzymes (ALT, AST) by 46%-55% in 12 weeks [21].
This registered real-world study is one of the first of its kind in the herbal segment, involving a large patient population with varied hepatic disorders with certain credibility in terms of standards and process of clinical research.The study was multicentric in nature and involved investigators from both allopathic and ayurvedic disciplines of medicine, to ensure variability and minimize the bias when the entire set of patient population is considered.The study used Oracle clinical remote data capture system which is 21 CFR part 11 compliant electronic data capture software, which ensures the credibility and integrity of the data.All AEs were coded using MedDRA, which further strengthens the assessments and reporting of safety in any study.The severity of adverse events was assessed through CTCAE, Version 5.0.All biochemical and hematological assessments were carried out at an accredited central laboratory to ensure uniformity, reliability, and accuracy of data.
While this phase IV study demonstrated the hepatoprotective effects and good tolerability of Liv.52 in patients with various hepatic disorders, the outcome should be interpreted carefully keeping in mind some notable limitations.One major limitation was the open-label design without placebo control, which could introduce bias in inference for the effectiveness of the product.Additionally, the diagnosis of the patients was made based on the available history and evidence at the investigator's discretion.For example, NAFLD was not confirmed by fibro scan or biopsy in the patient population, which is the gold standard for diagnosis of such patients.The study also did not account for the potential confounding effects of diet, lifestyle, and alcohol abstinence (especially in the alcoholic liver disease group), which could have played an important role in managing such disorders.However, considering the nature of the study, these limitations are acceptable, making it difficult to draw definitive conclusions about Liv.52's effectiveness in the management of these patients.Therefore, the outcome should be considered as its possible role in symptomatic improvement and supportive treatment with a fairly acceptable safety profile of the product.Larger, sample size-driven controlled studies with strict diagnostic criteria and assessments as per recommended global therapeutic guidelines are warranted to further establish Liv.52's hepatoprotective role.Despite these limitations, the study provides real-world evidence supporting Liv.52's safety and potential benefits in varied hepatic disorders.

Conclusions
This large, multi-centre phase IV study provides real-world evidence that the polyherbal formulation of Liv.52 is an efficacious and safe option for patients with various hepatic disorders, including ALD, NAFLD, DIH, and viral hepatitis.Apart from limitations, which are inherited characteristics of such types of studies, some robust processes of clinical research were adopted in this study.Treatment with Liv.52 for 12 weeks led to significant improvement in clinical symptoms, liver enzyme levels, and health-related QOL across different patient subgroups.Despite many limitation factors, statistically significant improvement in LFT parameters along with favorable trends in terms of signs, symptoms, and QOL in the current study are encouraging.With a favorable safety profile (with special reference to the safe nephrology profile, which is an emerging concern with many herbal products) as demonstrated in the study, Liv.52 emerges as a promising complementary or alternative therapeutic option for managing chronic liver diseases of mild to moderate severity.Although this trend is encouraging in terms of symptomatic improvement, improvement in liver parameters, and QOL in 12 weeks, larger duration studies with specific indications and endpoints based on therapeutic hepatology guidelines are warranted for further validation of these outcomes.

FIGURE 4 :
FIGURE 4: Impact on Anorexia at EOS (Per Protocol analysis set)

TABLE 4 : Investigator, Site Details, Ethics committee and Approval date
*Dropped **No enrollmentOut of 40 total sites, 2 sites were dropped before site initiation.Further one site had no enrollment, hence there were only 37 active sites in the study.